Cellular automaton-based model for radiation-induced bystander effects

Abstract

BackgroundThe radiation-induced bystander effect is a biological response observed in non-irradiated cells surrounding an irradiated cell. The bystander effect is known to be induced by two intercellular signaling pathways, the medium-mediated pathway (MDP) and the gap junctional pathway (GJP). To investigate the relative contribution of each signaling pathway, we have developed a mathematical model of the cellular response through these two pathways, with a particular focus on cell-cycle modification.MethodsThe model is based on a cellular automaton and consists of four components: (1) irradiation, (2) generation and diffusion of intercellular signals, (3) induction of DNA double-strand breaks (DSBs), and (4) cell-cycle modification or cell death. The intercellular signals are generated in and released from irradiated cells. The signals through the MDP and the GJP are modeled independently based on diffusion equations. The irradiation and both signals raise the number of DSBs, which determines transitions of cellular states, such as cell-cycle arrest or cell death.ResultsOur model reproduced fairly well previously reported experimental data on the number of DSBs and cell survival curves. We examined how radiation dose and intercellular signaling dynamically affect the cell cycle. The analysis of model dynamics for the bystander cells revealed that the number of arrested cells did not increase linearly with dose. Arrested cells were more efficiently accumulated by the GJP than by the MDP.ConclusionsWe present here a mathematical model that integrates various bystander responses, such as MDP and GJP signaling, DSB induction, cell-cycle arrest, and cell death. Because it simulates spatial and temporal conditions of irradiation and cellular characteristics, our model will be a powerful tool to predict dynamical radiobiological responses of a cellular population in which irradiated and non-irradiated cells co-exist.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0235-2) contains supplementary material, which is available to authorized users.

Clinically Relevant Radiation Exposure Differentially Impacts Forms of Cell Death in Human Cells of the Innate and Adaptive Immune System

“…In addition, cells might be affected by irradiated cells in close proximity even though they were not hit themselves. Those nontargeted or bystander effects are triggered by direct cell–cell communications or the release of signal molecules [ 14 , 15 ].…”

No Intercellular Regulation of the Cell Cycle among Human Cervical Carcinoma HeLa Cells Expressing Fluorescent Ubiquitination-Based Cell-Cycle Indicators in Modulated Radiation Fields

“…These well-documented responses are collectively known as the non-targeted radiation effects, although the underlying molecular mechanisms remain to be determined [ 1 ]. Several studies have shown significant alterations in cell survival in vitro in spatially modified radiation fields, experimentally [ 2 , 3 , 4 ] and theoretically [ 5 , 6 , 7 ]. This impact on cell survival is partially driven by intercellular signaling via gap junctions or soluble factors between irradiated cells and non-irradiated cells in living systems [ 8 , 9 , 10 , 11 ].…”

Coupling of cell fate selection model enhances DNA damage response and may underlie BE phenomenon

“…Powathil et al [10] propose a multiscale model incorporating spatiotemporal information of bystander, oxygen distribution and cell cycle phases. Cell cycle dynamics in BE signalling also has been studied by Hattori et al [11] via cellular automaton-based model. The integrated microdosimetric-kinetic model has been proposed to reveal the role of DNA repair kinetics in HRS [12].…”